EP0087957B1 - Neocarzinostatinkomplexe, Verfahren zu ihrer Herstellung und Antitumormittel, das diese Komplexe als aktive Komponente enhält - Google Patents

Neocarzinostatinkomplexe, Verfahren zu ihrer Herstellung und Antitumormittel, das diese Komplexe als aktive Komponente enhält Download PDF

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EP0087957B1
EP0087957B1 EP83301027A EP83301027A EP0087957B1 EP 0087957 B1 EP0087957 B1 EP 0087957B1 EP 83301027 A EP83301027 A EP 83301027A EP 83301027 A EP83301027 A EP 83301027A EP 0087957 B1 EP0087957 B1 EP 0087957B1
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neocarzinostatin
residue
sma
maleic acid
complexes
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French (fr)
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EP0087957A1 (de
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Hiroshi Maeda
Ryunosuke Kanamaru
Nakao Ishida
Toshihiko Yoshitake
Minoru Ueda
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Kayaku (also Trading As Kayaku A KK
MAEDA, HIROSHI
Kuraray Co Ltd
Yamanouchi Pharmaceutical Co Ltd
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Kayaku (also trading as Kayaku Antibiotics Research Co Ltd) KK
Kuraray Co Ltd
Yamanouchi Pharmaceutical Co Ltd
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Priority claimed from JP57031555A external-priority patent/JPS58149903A/ja
Priority claimed from JP58015075A external-priority patent/JPS59139396A/ja
Application filed by Kayaku (also trading as Kayaku Antibiotics Research Co Ltd) KK, Kuraray Co Ltd, Yamanouchi Pharmaceutical Co Ltd filed Critical Kayaku (also trading as Kayaku Antibiotics Research Co Ltd) KK
Priority to AT83301027T priority Critical patent/ATE23863T1/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
    • C08F8/32—Introducing nitrogen atoms or nitrogen-containing groups by reaction with amines
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S260/00—Chemistry of carbon compounds
    • Y10S260/47—Poisons, foods, or pharmaceuticals

Definitions

  • the present invention relates to novel neocarzinostatin complexes.
  • Neocarzinostatin is a proteinaceous anticancer agent produced in culture media in which Streptomyces carzinostaticus var. F-41 Kuroya is cultured (JP-B-67/21752) and US-A-3,334,022). With respect to the primary structure of this substance, the total number of amino acid residues and estimated molecular weight have been reported to be 109 and 10,700 respectively, by Hiroshi Maeda (Science, 178, 875-876 (1972) and Arch. Biochem. Biophys., 163, 379-385).
  • neocarzinostatin derivatives have been examined with the aim of lowering the toxicity and prolonging the activity of medicinal values possessed by neocarzinostatin, and with the aim of directing specific migration to the lymphatic system.
  • neocarzinostatin derivatives obtained by reacting two primary amino groups present in the molecule of neocarzinostatin with a partially hydrolyzed product of a water soluble styrene-maleic acid copolymer, possess the above described activities and this has been disclosed in US-A-4,182,752.
  • anticancer agents are desired to have a high affinity to the tumor in addition to the above described delivery of said agents into the lymphatic system in order to prevent the metastasis of cancer.
  • affinity of the agent to the tumor is high, the anticancer agent accumulates preferentially at tumor site, thus raising its concentration. This will also result in reducing the side effects in other organs.
  • neocarzinostatin complexes represented by the following formula (I): wherein n is an integer of 1-35, NCS represents neocarzinostatin residue, SMA represents a residue of a half-esterified styrene-maleic acid copolymer having an average molecular weight of 1,000-10,000 in which the maleic acid portion consists of the following units.
  • neocarzinostatin complexes of formula (I) have the same useful properties as the neocarzinostatin derivatives described in US ⁇ A ⁇ 4182752 and in addition are highly soluble in lipid media and can be used in the form of an oil soluble composition.
  • the complexes (I) of the present invention are administered as an oil soluble composition in a specific artery, the drug can be accumulated at the tumor site more selectively than by other routes of administration. Furthermore, the drug will stay in the tumor for a long period of time, and thus exert a high antitumor activity.
  • the complexes (I) of the present invention are water soluble as well as lipid soluble, so that the complexes can be systemically administered in the form of a water soluble composition, for example, by intravenous injection.
  • neocarzinostatin derivatives as provided by the complexes (I) of the present invention are considered to rely upon the use of the half-esterified styrene-maleic anhydride copolymers by means of which lipid solubility is conferred upon neocarzinostatin while maintaining its water solubility.
  • the present invention is characterized in that when the anticancer agent is administered by intravenous injection, it moves toward interstitial space from blood capillaries and uniquely migrates to lymphatic systems.
  • SMANX is used as an oil solution, it can be administered via a feeding artery and it is then deposited at the tumor site either in the capillaries or outside of the capillaries and is gradually released.
  • the molecular weight is preferred to be less than 80,000 and in order to obtain solubility in an oil base composition and unique delivery to the tumor or into the lymphatic system, the molecular weight is preferred to be more than 10,000.
  • the complex (I) of the present invention After the complex (I) of the present invention reaches the desired site in vivo, the complex directly or after a partial hydrolysis provides the neocarzinostatin to exert antitumor activity.
  • the complexes (I) of the present invention can be expected to form polyamino compounds and an immunological system in vivo.
  • the complexes (I) of the present invention have 1-35 molecules, generally 2-15 molecules of SMA per molecule of NCS.
  • the detail of the bonding form of NCS and SMA is unclear.
  • the structure of NCS has been already clarified in the above described literature [Science, 178,875-876 (1972)] and according to this publication, only two primary amino groups are present on the peptide chain, that is, alanine at the N-terminal and lysine at the twentieth position form the N-terminal, so that in the reaction of NCS with SMA, two primary amino groups of NCS can react with maleic anhydride residues of SMA.
  • NCS has a large number of secondary amino groups and hydroxyl groups, so that it is considered that there may be some kind of secondary bonds on account of some kind of intermolecular forces between above mentioned functional groups and SMA by which the complexes of formula (I) are formed.
  • the complexes of the present invention include ones in which either one or two primary amino groups of NCS form amide bonds with SMA and furthermore ones in which the above described functional groups form ester and amide bonds. Since the total number of the functional groups of NCS is 35, the content of SMA molecules per molecule of NCS may be 1-35 in the complexes. Practically, one molecule of NCS may bind with 2-15 molecules of SMA to form the complex.
  • SMA to be used in the present invention consists of the following main chain units, that is maleic acid half ester residues of the formula styrene residues of the formula and maleic anhydride residues of the formula
  • the SMA has a molecule weight of 1,000-10,000 and can be easily produced by half-esterifying styrene-maleic anhydride copolymers with mono-alcohols mentioned below following usual processes.
  • R is (1) a linear lower alkyl residue having 1-5 carbon atoms, such as methyl, ethyl, propyl, butyl and pentyl, preferably normal alkyl groups, more particularly n-butyl, or monohydroxy-alkyl ether residues of di- ortrihydric alcohols, for example (2) alkylene glycol mono-lower alkyl ether residue, wherein the alkylene group is ethylene or butylene and the lower alkyl group has 1-4 carbon atoms and is preferably ethyl or n-butyl, more particularly n-butyl, (3) polyethyleneglycol mono-alkyl ether residue represented by the formula R'-O-(C 2 H 4 0-+, wherein R' is a linear alkyl group having 1-8 carbon atoms, 2-,-5n:-520, or (4) glycerin dialkyl ether residue, wherein the alkyl group has 1-4 carbon atoms.
  • the content of maleic anhydride residue is SMA ranges from 0.1 per molecule to 50 mole %.
  • Maleic anhydride residue must be not less than 0.1 per molecule relative to the molecular weight of SMA.
  • the term "0.1 per molecule" of maleic anhydride residue used herein means that one anhydride group is present in ten SMA molecules.
  • the upper limit must be not greater than 50 mole % based on the total content of the anhydride residue of the initial SMA. To show the term "upper limit" more concretely, suppose firstly the molecular weight of SMA to be 1,000, then the content of the anhydride residue must not exceed 2.5 per molecule, and secondly the molecular weight to be 10,000, then said content must not exceed 25 per molecule.
  • the content of the anhydride residue is more preferably from 0.4 per molecule to 50 mole %. As the molecular weight increases, the content of maleic anhydride residue may also increase but if said content is too large, the reaction of maleic anhydride with NCS becomes complicated and an amount of the by-product becomes larger, so that the above described range is preferable. Maleic anhydride residues in SMA which are not reacted with NCS, become ring opened due to hydrolysis in the course of the reaction to form maleic acid residues. Thus, when the reaction is carried out in an aqueous medium, maleic anhydride residues are substantially not present in SMA residue in the complexes (I) of the present invention.
  • half ester used herein means that one of the two carboxyl groups attached to a maleic acid formed by opening the ring of maleic anhydride has been esterified and it is preferable that substantially all maleic acid residues other than maleic anhydride residues are half esterified but a part thereof may be free maleic acid residues.
  • the reaction temperature for producing the complexes of the present invention is generally lower than room temperature, preferably 0-15°C.
  • room temperature preferably 0-15°C.
  • the content of maleic anhydride residue in SMA is equal or greater than one per molecule, the products having complicated cross-linking structure may be produced, so that the reaction should be carried out at lower temperatures, such as, lower than 10°C.
  • NCS with SMA is one between polyfunctional polymers, so that it is impossible to specify the reaction sites of the reaction products and to show the molecular structure.
  • analysis of the mean structure of the reaction products can be made by the following experimental methods, such as, electrophoresis, gel permeation chromatography, gel filtration, infrared absorption spectrum, ultraviolet absorption spectrum and elemental analysis.
  • Neocarzinostatin complexes (I) of the present invention can be produced by reacting NCS with SMA.
  • the reaction is generally carried out as follows. NCS is dissolved in an aqueous solution of sodium bicarbonate and then powdery SMA is added thereto while stirring at room temperature or under cooling, preferably at a temperature lower than 15°C with SMA at equimolar or more, preferably three or more molar excess to NCS.
  • the complexes (I) of the present invention can be produced by mixing SMA solution in a water soluble organic solvent inert to maleic anhydride (for example acetonitrile, dioxane or tetrahydrofuran) and NCS dissolved in an aqueous solution of sodum bicarbonate. After an appropriate period of time, the solvent is removed by evaporation under a reduced pressure. It is considered that the complexes (I) of the present invention are produced by opening the ring of maleic anhydride residue and then reacting with the functional groups of NCS and 1-35 molecules of SMA can react with one molecule of NCS to form the complex but presumably 2-15 molecules of SMA generally react with NCS to form the complex.
  • a water soluble organic solvent inert for example acetonitrile, dioxane or tetrahydrofuran
  • NCS dissolved in an aqueous solution of sodum bicarbonate.
  • the formed complexes include not only the reaction products wherein one or two of two primary amino groups in NCS are reacted with SMA to form amide bonds but also SMA may be reacted with the other functional groups of NCS to form different types of bonds.
  • Complex :I) may be formed by non-covalent bonding between styrene and side chain aromatic hydrophobic rings in NCS as well as ionic bonding between carboxyl groups of SMA and positive charge of NCS such as that of arginine.
  • the above described reaction is carried out by dissolving NCS in an aqueous solution of sodium bicarbonate and adding SMA in the resulting solution but various salts resulting from sodium bicarbonate and excess SMA are contained in the reaction product due to the use of such a system, so that these substances are removed by a variety of means, such as dialysis or gel filtration.
  • the neocarzinostatin complexes (I) of the present invention can be submitted to practical use as medicaments in human therapy by local administration, such as the primary site of cancer and the area of tumor removal or resection, or by intracutaneous, subcutaneous, intramuscular, intravenous, intraarterial and oral administration, or by external application, such as applying or spraying to local site to be treated, suppository or intravesical instillation.
  • the dosages depend on administration routes, malignancy stage and grade of tumor, types of tumor, and conditions of patients. Further, the dosages depend on the purposes, such as the prevention of metastasis to lymph nodes after operation, or therapeutic treatment.
  • the complexes (I) of the present invention are preferably administered in a dosage of 0.01-10 mg/kg once a day for a period of week, or once or twice a week, or on consecutive days.
  • the dosage may be further increased.
  • the complexes (I) of the present invention can be suspended and solubilized in an X-ray oily contrast medium of Lipiodol (Ethiodol) (Made by Laboratoires André Guerbet (Paris, France), Lipiodol Ultra-Fluide: Fatty acid ethyl ester of iodized poppy seed oil, iodine content: 38 W/W) under ultrasonic wave.
  • an oil of the complex (I) of the present invention having 1-2 mg/1 ml of Lipiodol is applied in intraarterial administration, Lipiodol and the present complex would stay selectively in the tumor for a long period of time, so that the high antitumor activity is developed.
  • the complex (I) in Lipiodol By dissolving the complex (I) in Lipiodol, the size and local of the tumor can be observed by X-ray, and tomogram can be followed effectively even after one month.
  • the complexes (I) of the present invention are dissolved in 1-9% of aqueous sodium bicarbonate solution or alike.
  • aqueous sodium bicarbonate solution or alike.
  • the resulting styrene-maleic anhydride copolymer was deducted to be an alternate copolymer from the polymerizability of each monomer, and this structure was supported by the result of elemental analysis as well.
  • a number average molecular weight of this copolymer was determined by using acetonitrile as a solvent through a vapor pressure osmometry by means of a VPO apparatus made by KNAUER Co. and said value was 1760.
  • the resulting residue was washed with a mixture of n-hexane and acetone (volume ratio of 9: 1), and then dried under a reduced pressure to obtain a light yellow half butyl-esterified styrene-maleic anhydride copolymer wherein maleic anhydride rings have been partially retained.
  • the molecular weight was measured by the vapor pressure osmometry to be 2,200, and the average maleic anhydride ring content was calculated to be 0.75/molecule from the ratio of 0 1.780 1 D 700 of the infrared absorption spectrum.
  • the reaction solution was charged into a dialysis tube (Union Carbide Co., Chicago), and subjected to a dialysis in a 5 mM aqueous solution of sodium bicarbonate under pressure. After the dialysis at 4°C for 2 days exchanging several times of the 5 mM aqueous solution of sodium bicarbonate, a dialysis was further continued for 2 days in a 5 mM aqueous solution of sodium bicarbonate kept at 4°C, and then for 2 days in a 1.25 mM aqueous solution of ammonium bicarbonate kept at 4°C.
  • the reaction mixture after the dialysis was freeze-dried, and then the dried material was subjected three times to the operations of suspension in pure water, washing and collection of insoluble part by a centrifugal separator.
  • the above treated material was freeze-dried to obtain 0.15 g of a white fluffy solid of neocarzinostatin-half butyl-esterified styrene-maleic acid copolymer complex (SMANX).
  • SMANX neocarzinostatin-half butyl-esterified styrene-maleic acid copolymer complex
  • the infrared absorption spectrum (in KBr) of the resulting SMANX is shown in Fig. 1, and the infrared absorption spectra (in KBr) of the half butyl-esterified styrene-maleic anhydride copolymer are shown in Figs. 2 and 3, respectively.
  • the SMANX exhibited a molecular weight of about 43,000 as measured by polyacrylamide gel disc electrophoresis with sodium dodecyl sulfate (SDS), SMANX softens slightly at 230°C and begins to decompose at 250°C.
  • SMANX is different from both NCS and half butyl-esterified styrene-maleic anhydride copolymer, and is a unique entity.
  • test tube Into a test tube were added 10 g (0.0048 mole) of a styrene-maleic anhydride copolymer having a number average molecular weight of 2,100 as measured by the vapor pressure osmometry, 0.1 g of lithium acetate and a given amount of each of alcohol and dioxane, and after the test tube was fused to seal shake for 24 hours at room temperature. The homogeneous solution was heated at 90°C for 15 hours and then cooled to room temperature. The reaction solution was taken out from the test tube, diluted with dioxane into 2 times of the original volume, and then freeze-dried.
  • the dried material was further dried at 60°C for 24 hours in vacuo and light yellow flaky product (SMA) was obtained wherein maleic anhydride rings have been partially retained. Half of all the remaining carboxyl were the half-esterified SMA. The amount of anhydride residue remained in the resulting SMA was quantitatively analyzed from the ratio in the optical densities at wave numbers of 1,780 cm- 1 and 700 cm- 1 by the infrared absorption spectrum method. The type and amount of alcohols and dioxane, the average molecular weight of the resulting SMA measured by the vapor pressure osmometry and the content of anhydride component remaining in the SMA are shown in Table 2.
  • the amount of the residual free amino group of the complexes according to the present invention was measured as follows. An aliquot of the solution after completion of the reaction was diluted with water, then the primary amino group was reacted with trinitrobenzene sulfonic acid, and the amount of the resulting nitrobenzene derivative was determined by a spectrophotometer. Results of elemental analysis of the resulting complexes are shown in Table 4. Infrared absorption spectra of the complexes measured by the KBr tablet method are shown in Figs. 4a-4d. Figs. 5a-5d show gel permeation chromatograms of the complexes measured at a pH of 7.9 by using a G-3000 SW column made by Toyo Soda Co.
  • Fig. 6 shows a gel permeation chromatogram of NCS.
  • Figs. 7a-7d show ultraviolet and visible ray absorption spectra of the complexes in a 0.5 M sodium bicarbonate. Furthermore, the solubility of the complexes in various solvents is shown in Table 5.
  • neocarzinostatin 0.5 g was dissolved in 100 ml of a 0.5 M aqueous solution of sodium bicarbonate at a temperature of 5-8°C in the dark and 2.0 g of the above described partially butyl-esterified styrene-maleic anhydride copolymer was added thereto in several lots over 3 hours while stirring and the mixture was thoroughly stirred until the copolymer was completely dissolved. After the dissolution, the reaction mixture was left to stand at a temperature of 4-6C for 16 hours and the subsequent operation was followed to Examples 2-5 and the reaction product was finally freeze-dried to obtain white fluffy SMANX. In this case, the reaction percentage of amino group was 50.5 mol % and the yield of the complex was 72.9%.
  • the molecular weight estimated by SDS disc gel electrophoresis was 36,000 and the elemental analytical value was as follows.
  • N 4.07 wt %
  • C 59.28 wt %
  • H 6.18 wt %.
  • the pharmacological activity of the thus obtained SMANX was as follows.
  • the dosage of at least 0.025 mg/kg apparently shows antitumor activity.
  • the dosage of 0.25-1 mg/kg is low in activity and 2 mg/kg shows the apparent surviving activity.

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Claims (13)

1. Neocarzinostatinkomplexe, welche durch die Formel
Figure imgb0022
dargestellt werden, worin n eine ganze Zahl von 1-35 bedeutet, NCS einen Neocarzinostatinrest darstellt, SMA einen Rest eines halbveresterten Styrol-Maleinsäure-Copolymers mit einem durchschnittlichen Molekulargewicht von 1000 bis 10000 bedeutet, worin der Maleinsäureteil aus den folgenden Einheiten besteht, nämlich
(1) einem an NCS gebundenen Maleinsäurerest
Figure imgb0023
(2) einem freien oder durch nicht-kovalente Bindung an NCS gebundenen Maleinsäurerest
Figure imgb0024
mit der Maßgabe, daß die Gesamtmenge der oben beschriebenen Maleinsäurereste (1) und (2) von einem Durchschnittsgehalt von 0,1 pro Molekül bis 50 Mol-% an SMA reicht, und
(3) einem halbveresterten Maleinsäurerest
Figure imgb0025
worin R ein Rest eines einwertigen Alkohols oder ein Rest eines Monohydroxyalkylethers eines zwei- oder dreiwertigen Alkohols ist.
2. Neocarzinostatinkomplexe nach Anspruch 1, worin die Gesamtmenge der Maleinsäurerest-Einheiten (1) und (2) ein Durchschnittsgehalt von 0,1 bis weniger als 1 pro Molekül SMA ist.
3. Neocarzinostatinkomplexe nach Anspruch 1, worin die Gesamtmenge der Maleinsäurerest-Einheiten (1) und (2) ein Durchschnittsgehalt von 0,1 bis 0,8 pro Molekül SMA ist.
4. Neocarzinostatinkomplexe nach Anspruch 1, worin die Gesamtmenge der Maleinsäurerest-Einheiten (1) und (2) ein Durchschnittsgehalt von 1 pro Molekül bis 50 Mol-% SMA ist.
5. Neocarzinostatinkomplexe nach Anspruch 1, worin die Gesamtmenge an Maleinsäurerest-Einheiten (1) und (2) ein Durchschnittsgehalt von 0,4 pro Molekül bis 50 Mol-% SMA ist.
6. Neocarzinostatinkomplexe nach Anspruch 1 bis 5, worin R in dem halbveresterten Maleinsäurerest (3) ein lineare Alkylgruppe mit 1 bis 5 Kohlenstoffatomen ist.
7. Neocarzinostatinkomplexe nach einem der Ansprüche 1 bis 5, worin R in dem halbveresterten Maleinsäurerest (3) eine Ethylenglykolmonoalkyletherrest ist, worin die Alkylgruppe 1 bis 4 Kohlenstoffatome besitzt.
8. Neocarzinostatinkomplexe nach einem der Ansprüche 1 bis 5, worin R in dem halbveresterten Maleinsäurerest (3) ein Polyethylenglykolmonoalkyletherrest der Formel
Figure imgb0026
ist, worin R' eine lineare Alkylgruppe mit 1 bis 8 Kohlenstoffatomen ist und n eine ganze Zahl von 2 bis 20 ist.
9. Neocarzinostatinkomplexe nach einem der Ansprüche 1 bis 5, worin R in dem halberesterten Maleinsäurerest (3) ein Glycerindialkyletherrest ist, worin jede Alkylgruppe 1 bis 4 Kohlenstoffatome aufweist.
10. Antitumormittel, welches einen Neocarzinostatinkomplex nach einem der voranstehenden Ansprüche als eine aktive Komponente enthält.
11. Verfahren zur Herstellung eines Neocarzinostatinkomplexes nach einem der Ansprüche 1 bis 9, wobei in diesem Verfahren Neocarzinostatin mit einem halbveresterten Styrol-Maleinsäureanhydrid-Copolymer mit einem durchschnittlichen Molekulargewicht von 1000 bis 10000 und einem Maleinsäureanhydridrest mit von einem Durchschnittsgehalt von 0,1 pro Molekül bis 50 Mol-% SMA umgesetzt wird.
12. Verfahren nach Anspruch 11, worin das halbveresterte Styrol-Maleinsäureanhydrid-Copolymer einen Maleinsäureanhydridrest eines Durchschnittsgehalts von 0,1 bis weniger als 1 pro Molekül SMA aufweist.
13. Verfahren nach Anspruch 11, worin das halbveresterte Styrol-Maleinsäureanhydrid-Copolymer einen Maleinsäureanhydridrest mit einem Durchschnittsgehalt von 1 pro Molekül bis 50 Mol-% SMA aufweist.
EP83301027A 1982-02-27 1983-02-25 Neocarzinostatinkomplexe, Verfahren zu ihrer Herstellung und Antitumormittel, das diese Komplexe als aktive Komponente enhält Expired EP0087957B1 (de)

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AT83301027T ATE23863T1 (de) 1982-02-27 1983-02-25 Neocarzinostatinkomplexe, verfahren zu ihrer herstellung und antitumormittel, das diese komplexe als aktive komponente enhaelt.

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JP31555/82 1982-02-27
JP57031555A JPS58149903A (ja) 1982-02-27 1982-02-27 ネオカルチノスタチン複合体の製造法
JP58015075A JPS59139396A (ja) 1983-01-31 1983-01-31 ネオカルチノスタチン複合体の製造方法
JP15075/83 1983-01-31

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1627645A1 (de) * 2003-05-26 2006-02-22 Hiroshi Maeda Antitumorales mittel und verfahren zu seiner herstellung

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* Cited by examiner, † Cited by third party
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JPS6075499A (ja) * 1983-08-08 1985-04-27 Kuraray Co Ltd ネオカルチノスタチン誘導体及びその製造法
JPS6075432A (ja) * 1983-08-08 1985-04-27 Kuraray Co Ltd ネオカルチノスタチン誘導体及びその製造方法
JP2556865B2 (ja) * 1986-09-19 1996-11-27 山之内製薬株式会社 ネオカルチノスタチン誘導体の非注射投与用組成物
US5389366A (en) * 1986-09-19 1995-02-14 Yamanouchi Pharmaceutical Co., Ltd. Neocarzinostatin derivative composition for oral administration
CA1327161C (en) * 1987-09-01 1994-02-22 Mitsugu Kobayashi Lyophilized pharmaceutical composition of neocarzinostatin derivative
US9375203B2 (en) 2002-03-25 2016-06-28 Kieran Murphy Llc Biopsy needle
US7927368B2 (en) * 2002-03-25 2011-04-19 Kieran Murphy Llc Device viewable under an imaging beam
US20030181810A1 (en) 2002-03-25 2003-09-25 Murphy Kieran P. Kit for image guided surgical procedures
US7871818B2 (en) * 2003-01-31 2011-01-18 Roche Madison Inc. Membrane active polymers
WO2006112361A1 (ja) * 2005-04-18 2006-10-26 Hiroshi Maeda 高分子型癌治療用医薬およびその製造方法
GB2426703B (en) * 2005-05-31 2007-09-19 Malvern Cosmeceutics Ltd Compositions
GB0601251D0 (en) * 2006-01-21 2006-03-01 Babraham Bioscience Technologi Protein solubilisation composition
EP3072910A4 (de) 2013-11-19 2018-02-21 Hiroshi Maeda Derivat eines styrol-maleinsäure-copolymers
GB201909680D0 (en) 2019-07-05 2019-08-21 Malvern Cosmeceutics Ltd Hypercoiling polymer derivatives

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3085994A (en) * 1959-10-30 1963-04-16 Sinclair Research Inc Chain terminated copolymer of styrene and maleic anhydride of low solution viscosity
US3121043A (en) * 1960-05-11 1964-02-11 Scient Associates Inc Sustained release pharmaceutical preparation and methods for making same
US3245933A (en) * 1960-05-19 1966-04-12 Sinclair Research Inc Styrene-maleic anhydride copolymers cross-linked with aliphatic polyhydroxy compounds
JPS6017206B2 (ja) * 1977-03-24 1985-05-01 浩 前田 ネオカルチノスタチン誘導体の製造法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1627645A1 (de) * 2003-05-26 2006-02-22 Hiroshi Maeda Antitumorales mittel und verfahren zu seiner herstellung
EP1627645A4 (de) * 2003-05-26 2008-12-24 Hiroshi Maeda Antitumorales mittel und verfahren zu seiner herstellung

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EP0087957A1 (de) 1983-09-07
US4732933A (en) 1988-03-22
CA1214458A (en) 1986-11-25
DE3367921D1 (en) 1987-01-15

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